Cytokines are pleiotropic molecules that elicit their effect locally or systematically in an autocrine or paracrine manner. Recent evidence suggests an important role for cytokines in cardiovascular remodeling in heart failure. Consequently, the overall hypothesis of the present proposal is that the newly discovered cytokines interleukin-15 (IL-15) and interleukin-18 (IL-18) play a role in cardiac cell inflammation, growth, ECM remodeling, and/or survival either alone or synergically with other cytokines or environmental factors (i.e. hypoxia/ischemia). Specific aim 1 will test the hypothesis that IL-1 5 and IL-1 8 play a role in cardiac cell inflammation. Specific aim 2 will test the hypothesis that IL-15 and IL-18 play a role in cardiac cell growth and survival. Specific aim 3 will test whether hypoxia, a major component of ischemia, can modulate IL-15 and IL-18 expression and signaling pathways. In relation to each specific aim, we shall delineate the molecular mechanisms and the specific signaling pathways mediating IL-15 and IL-18 action and whether there is a synergistic action or cross talk. Specific aim 4 will determine the cardiac specific role of IL-15 and IL-18 in vivo and whether selective inhibition prevents ischemia/reperfusion induced injury or cardiac remodeling after MI. The overall goal of this project is to understand the signal transduction pathways required for IL-15 and IL-18 in mediating cardiac cell function in vitro and in vivo. The study will be performed using an established in vitro model of cultured neonatal cardiac myocytes and fibroblasts, and in vivo models of ischemia and heart failure using state of the art techniques. We anticipate that this investigation will generate new information, which will enhance our understanding of the roles of these novel immunomodulators in cardiac cells. This work will enable us to devise further in vivo studies targeting IL-15 or IL-18 signaling which may help define their pathophysiological role in the setting of ischemia and heart failure. The work may reveal new therapeutic targets to modulate or prevent ischemic disease, cardiac remodeling, and heart failure.